AT395589B - Antihypercholesterinaemische tetrazol-verbindungen - Google Patents

Antihypercholesterinaemische tetrazol-verbindungen Download PDF

Info

Publication number: AT395589B
Authority: AT; Austria
Prior art keywords: methyl; tetrazol; bis; dihydroxy; fluorophenyl
Prior art date: 1987-02-25

Application number

AT0046188A

Other languages

German (de)

English (en)

Other versions

ATA46188A (de

Original Assignee

Bristol Myers Squibb Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1987-02-25

Filing date

1988-02-24

Publication date

1993-01-25

1988-02-24 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

1992-02-28 Priority to AT0038292A priority Critical patent/AT401175B/de

1992-02-28 Priority to AT0037992A priority patent/AT401518B/de

1992-06-15 Publication of ATA46188A publication Critical patent/ATA46188A/de

1993-01-25 Application granted granted Critical

1993-01-25 Publication of AT395589B publication Critical patent/AT395589B/de

Links

-1 TETRAZOLE COMPOUNDS Chemical class 0.000 title claims description 75
150000001875 compounds Chemical class 0.000 claims description 234
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 151
238000006243 chemical reaction Methods 0.000 claims description 67
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 52
150000003839 salts Chemical class 0.000 claims description 47
239000011734 sodium Substances 0.000 claims description 41
229910052739 hydrogen Inorganic materials 0.000 claims description 38
239000001257 hydrogen Substances 0.000 claims description 38
238000000034 method Methods 0.000 claims description 37
231100000252 nontoxic Toxicity 0.000 claims description 37
230000003000 nontoxic effect Effects 0.000 claims description 37
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 34
229910052708 sodium Inorganic materials 0.000 claims description 34
150000002431 hydrogen Chemical class 0.000 claims description 29
125000000217 alkyl group Chemical group 0.000 claims description 27
239000002253 acid Substances 0.000 claims description 22
230000015572 biosynthetic process Effects 0.000 claims description 22
238000002360 preparation method Methods 0.000 claims description 22
150000002596 lactones Chemical class 0.000 claims description 20
150000001768 cations Chemical class 0.000 claims description 19
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
239000003960 organic solvent Substances 0.000 claims description 17
239000012279 sodium borohydride Substances 0.000 claims description 16
229910000033 sodium borohydride Inorganic materials 0.000 claims description 16
125000004185 ester group Chemical group 0.000 claims description 13
150000002148 esters Chemical group 0.000 claims description 12
230000008569 process Effects 0.000 claims description 11
229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical class 0.000 claims description 9
125000003545 alkoxy group Chemical group 0.000 claims description 8
239000011737 fluorine Substances 0.000 claims description 8
229910052731 fluorine Inorganic materials 0.000 claims description 8
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
239000000460 chlorine Substances 0.000 claims description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
159000000000 sodium salts Chemical class 0.000 claims description 7
WMHRYMDGHQIARA-UHFFFAOYSA-N 4-hydroxyoxan-2-one Chemical compound OC1CCOC(=O)C1 WMHRYMDGHQIARA-UHFFFAOYSA-N 0.000 claims description 6
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
229910052801 chlorine Inorganic materials 0.000 claims description 6
230000007062 hydrolysis Effects 0.000 claims description 5
238000006460 hydrolysis reaction Methods 0.000 claims description 5
IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
229910000085 borane Inorganic materials 0.000 claims description 4
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
150000001718 carbodiimides Chemical class 0.000 claims description 3
229910052740 iodine Inorganic materials 0.000 claims description 3
ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims description 3
229910052700 potassium Inorganic materials 0.000 claims description 3
239000011591 potassium Substances 0.000 claims description 3
UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 3
MJJWVTSDHVPFSY-OALUTQOASA-N (4S,6R)-6-[4,4-bis(4-fluorophenyl)-3-(2-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NC(C(C=C[C@@H]2OC(=O)C[C@@H](O)C2)=C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=N1 MJJWVTSDHVPFSY-OALUTQOASA-N 0.000 claims description 2
RBLTZEADLBSLLL-UHFFFAOYSA-N 2-(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyltetrazol-5-yl)undeca-6,8,10-trienoic acid Chemical compound FC1=CC=C(C=C1)C(C(=O)O)C(CC(C=CC=CC(=C)C1=NN=NN1C)O)O RBLTZEADLBSLLL-UHFFFAOYSA-N 0.000 claims description 2
HPFIYXJJZZWEPC-UHFFFAOYSA-N 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(C=CC(O)CC(O)CC(O)=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 HPFIYXJJZZWEPC-UHFFFAOYSA-N 0.000 claims description 2
PKCKEZQWMULFSP-UHFFFAOYSA-N 9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyltetrazol-5-yl)-5-oxonona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(C=CC(=O)CC(O)CC(O)=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 PKCKEZQWMULFSP-UHFFFAOYSA-N 0.000 claims description 2
230000003213 activating effect Effects 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
FVEPTWMEHOWRQS-UHFFFAOYSA-N 2-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(=C)C=CC(O)CC(O)C(C(O)=O)C1=CC=C(F)C=C1 FVEPTWMEHOWRQS-UHFFFAOYSA-N 0.000 claims 2
MBBMXKCOQGGNBU-OALUTQOASA-N (4S,6R)-6-[4,4-bis(4-fluoro-2-methylphenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound FC1=CC(=C(C=C1)C(=C(C=C[C@H]1C[C@@H](CC(O1)=O)O)C1=NN=NN1C)C1=C(C=C(C=C1)F)C)C MBBMXKCOQGGNBU-OALUTQOASA-N 0.000 claims 1
WUFHJAYBMLFGMR-UHFFFAOYSA-N 2-(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CC1=CC(F)=CC=C1C(C(O)=O)C(O)CC(O)C=CC(=C)C1=NN=NN1C WUFHJAYBMLFGMR-UHFFFAOYSA-N 0.000 claims 1
CSIQUBMEJWWECT-UHFFFAOYSA-N 2-(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound FC1=CC=C(C=C1)C(C(=O)O)C(CC(C=CC(=C)C=1N=NN(N1)C)O)O CSIQUBMEJWWECT-UHFFFAOYSA-N 0.000 claims 1
NPNUEPHXWBLWBS-UHFFFAOYSA-N 3,5-dihydroxy-2-(4-methoxyphenyl)-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound COC1=CC=C(C=C1)C(C(=O)O)C(CC(C=CC(=C)C1=NN=NN1C)O)O NPNUEPHXWBLWBS-UHFFFAOYSA-N 0.000 claims 1
AHTCTEWMURVOLA-UHFFFAOYSA-N 3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(=C)C=CC(O)CC(O)CC(O)=O AHTCTEWMURVOLA-UHFFFAOYSA-N 0.000 claims 1
MGSJIZDEFXXIQN-UHFFFAOYSA-N 9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid Chemical compound CC1=CC(F)=CC=C1C(C=1C(=CC(F)=CC=1)C)=C(C=CC(O)CC(O)CC(O)=O)C1=NN=NN1C MGSJIZDEFXXIQN-UHFFFAOYSA-N 0.000 claims 1
KOERGCFEGUXLET-UHFFFAOYSA-N 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoic acid hydrate Chemical class O.FC1=CC=C(C=C1)C(=C(C=CC(CC(CC(=O)O)O)O)C1=NN=NN1C)C1=CC=C(C=C1)F KOERGCFEGUXLET-UHFFFAOYSA-N 0.000 claims 1
DVWJMSNCSNYDDS-UHFFFAOYSA-N 9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)-9-phenylnona-6,8-dienoic acid Chemical compound CN1N=NN=C1C(C=CC(O)CC(O)CC(O)=O)=C(C=1C=CC(F)=CC=1)C1=CC=CC=C1 DVWJMSNCSNYDDS-UHFFFAOYSA-N 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
239000000243 solution Substances 0.000 description 212
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 155
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 144
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
239000000203 mixture Substances 0.000 description 65
229910001868 water Inorganic materials 0.000 description 61
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
235000019439 ethyl acetate Nutrition 0.000 description 57
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
238000005481 NMR spectroscopy Methods 0.000 description 45
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
230000002829 reductive effect Effects 0.000 description 44
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
239000000047 product Substances 0.000 description 41
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 36
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
238000002329 infrared spectrum Methods 0.000 description 30
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
239000002904 solvent Substances 0.000 description 28
239000012044 organic layer Substances 0.000 description 25
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
239000007787 solid Substances 0.000 description 24
101150041968 CDC13 gene Proteins 0.000 description 23
XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 23
239000011541 reaction mixture Substances 0.000 description 23
239000000741 silica gel Substances 0.000 description 23
229910002027 silica gel Inorganic materials 0.000 description 23
150000001299 aldehydes Chemical class 0.000 description 22
238000003756 stirring Methods 0.000 description 20
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 19
239000003921 oil Substances 0.000 description 19
238000010898 silica gel chromatography Methods 0.000 description 18
LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 18
235000012000 cholesterol Nutrition 0.000 description 17
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
230000005764 inhibitory process Effects 0.000 description 13
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 12
238000012360 testing method Methods 0.000 description 12
239000003153 chemical reaction reagent Substances 0.000 description 11
230000009467 reduction Effects 0.000 description 11
238000010992 reflux Methods 0.000 description 11
239000000725 suspension Substances 0.000 description 11
229960000583 acetic acid Drugs 0.000 description 10
229910052786 argon Inorganic materials 0.000 description 10
238000001816 cooling Methods 0.000 description 10
238000000926 separation method Methods 0.000 description 10
238000004809 thin layer chromatography Methods 0.000 description 10
102000004190 Enzymes Human genes 0.000 description 9
108090000790 Enzymes Proteins 0.000 description 9
238000010828 elution Methods 0.000 description 9
229940088598 enzyme Drugs 0.000 description 9
239000010410 layer Substances 0.000 description 9
FTRDGZNVVMEGRC-UHFFFAOYSA-M sodium;9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyltetrazol-5-yl)-5-oxonona-6,8-dienoate Chemical compound [Na+].CN1N=NN=C1C(C=CC(=O)CC(O)CC([O-])=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 FTRDGZNVVMEGRC-UHFFFAOYSA-M 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
229930182558 Sterol Natural products 0.000 description 8
239000007864 aqueous solution Substances 0.000 description 8
239000000284 extract Substances 0.000 description 8
239000005457 ice water Substances 0.000 description 8
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
229910052757 nitrogen Inorganic materials 0.000 description 8
239000000843 powder Substances 0.000 description 8
238000000746 purification Methods 0.000 description 8
150000003432 sterols Chemical class 0.000 description 8
235000003702 sterols Nutrition 0.000 description 8
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 7
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
239000012267 brine Substances 0.000 description 7
210000004027 cell Anatomy 0.000 description 7
238000004440 column chromatography Methods 0.000 description 7
239000003480 eluent Substances 0.000 description 7
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
210000004185 liver Anatomy 0.000 description 7
PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 7
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
239000000126 substance Substances 0.000 description 7
239000006188 syrup Substances 0.000 description 7
235000020357 syrup Nutrition 0.000 description 7
CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 6
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 6
CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 6
241000700159 Rattus Species 0.000 description 6
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
150000001298 alcohols Chemical class 0.000 description 6
RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
230000008020 evaporation Effects 0.000 description 6
238000002474 experimental method Methods 0.000 description 6
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
229910000104 sodium hydride Inorganic materials 0.000 description 6
229910052938 sodium sulfate Inorganic materials 0.000 description 6
235000011152 sodium sulphate Nutrition 0.000 description 6
125000001424 substituent group Chemical group 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
SHJCSBYIGNIKHH-UHFFFAOYSA-N (4-fluorophenyl) 3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound CN1N=NN=C1C(=C)C=CC(O)CC(O)CC(=O)OC1=CC=C(F)C=C1 SHJCSBYIGNIKHH-UHFFFAOYSA-N 0.000 description 5
102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 5
108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 5
208000035150 Hypercholesterolemia Diseases 0.000 description 5
208000031226 Hyperlipidaemia Diseases 0.000 description 5
241001465754 Metazoa Species 0.000 description 5
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
230000029936 alkylation Effects 0.000 description 5
238000005804 alkylation reaction Methods 0.000 description 5
239000002585 base Substances 0.000 description 5
239000012965 benzophenone Substances 0.000 description 5
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
239000003112 inhibitor Substances 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
238000007273 lactonization reaction Methods 0.000 description 5
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BVBBICKLCGKYME-UHFFFAOYSA-N ethoxy(diethyl)borane Chemical compound CCOB(CC)CC BVBBICKLCGKYME-UHFFFAOYSA-N 0.000 description 1
ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
AGYCYFODYHJUTE-UHFFFAOYSA-N ethyl 7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-(2-propan-2-yltetrazol-5-yl)hept-6-enoate Chemical compound N1=NN(C(C)C)N=C1C(C(O)CC(O)CC(=O)OCC)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 AGYCYFODYHJUTE-UHFFFAOYSA-N 0.000 description 1
RXBSRCOOHVACTH-UHFFFAOYSA-N ethyl 7,7-bis(4-fluorophenyl)-5-hydroxy-3-oxo-6-(2-propan-2-yltetrazol-5-yl)hept-6-enoate Chemical compound N1=NN(C(C)C)N=C1C(C(O)CC(=O)CC(=O)OCC)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 RXBSRCOOHVACTH-UHFFFAOYSA-N 0.000 description 1
AGNVQAZYLJPGJV-UHFFFAOYSA-N ethyl 8-(1-ethyltetrazol-5-yl)-9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxonona-6,8-dienoate Chemical compound N=1N=NN(CC)C=1C(C=CC(O)CC(=O)CC(=O)OCC)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 AGNVQAZYLJPGJV-UHFFFAOYSA-N 0.000 description 1
JPBVJGNVCGVKCS-UHFFFAOYSA-N ethyl 8-(2-ethyltetrazol-5-yl)-9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxonona-6,8-dienoate Chemical compound N1=NN(CC)N=C1C(C=CC(O)CC(=O)CC(=O)OCC)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 JPBVJGNVCGVKCS-UHFFFAOYSA-N 0.000 description 1
REUPHELOOCTNKC-UHFFFAOYSA-N ethyl 9,9-bis(4-fluoro-3-methylphenyl)-5-hydroxy-8-(1-methyltetrazol-5-yl)-3-oxonona-6,8-dienoate Chemical compound N=1N=NN(C)C=1C(C=CC(O)CC(=O)CC(=O)OCC)=C(C=1C=C(C)C(F)=CC=1)C1=CC=C(F)C(C)=C1 REUPHELOOCTNKC-UHFFFAOYSA-N 0.000 description 1
UNWFVUXOWVALTK-UHFFFAOYSA-N ethyl 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-1,3-dihydrotetrazol-5-yl)nona-6,8-dienoate Chemical compound N=1NN(C)NC=1C(C=CC(O)CC(O)CC(=O)OCC)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 UNWFVUXOWVALTK-UHFFFAOYSA-N 0.000 description 1
DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
201000005884 exanthem Diseases 0.000 description 1
230000007717 exclusion Effects 0.000 description 1
238000000855 fermentation Methods 0.000 description 1
230000004151 fermentation Effects 0.000 description 1
239000003337 fertilizer Substances 0.000 description 1
239000000945 filler Substances 0.000 description 1
238000009472 formulation Methods 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
238000005194 fractionation Methods 0.000 description 1
239000007789 gas Substances 0.000 description 1
238000004817 gas chromatography Methods 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
239000000499 gel Substances 0.000 description 1
238000007429 general method Methods 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
229920000669 heparin Polymers 0.000 description 1
HHLIJJJAKAFXJB-UHFFFAOYSA-N hepta-4,6-dienoic acid Chemical compound OC(=O)CCC=CC=C HHLIJJJAKAFXJB-UHFFFAOYSA-N 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
230000003301 hydrolyzing effect Effects 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
230000003516 hyperlipidaemic effect Effects 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
230000003834 intracellular effect Effects 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
239000011630 iodine Substances 0.000 description 1
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
108010052968 leupeptin Proteins 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
238000005567 liquid scintillation counting Methods 0.000 description 1
239000006194 liquid suspension Substances 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
229910003002 lithium salt Inorganic materials 0.000 description 1
159000000002 lithium salts Chemical class 0.000 description 1
229960004844 lovastatin Drugs 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
238000005360 mashing Methods 0.000 description 1
MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
MREHOEYVFVTIMU-BUHFOSPRSA-N methyl (6e)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)-9,9-diphenylnona-6,8-dienoate Chemical compound N=1N=NN(C)C=1C(/C=C/C(O)CC(O)CC(=O)OC)=C(C=1C=CC=CC=1)C1=CC=CC=C1 MREHOEYVFVTIMU-BUHFOSPRSA-N 0.000 description 1
HVXZKDMZRUSNTE-UHFFFAOYSA-N methyl 2-(4-penta-1,3-dienyl-1,5-dioxaspiro[5.5]undecan-2-yl)acetate Chemical compound O1C(CC(=O)OC)CC(C=CC=CC)OC11CCCCC1 HVXZKDMZRUSNTE-UHFFFAOYSA-N 0.000 description 1
HQSOLRBHGJZPST-UHFFFAOYSA-N methyl 2-(6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate Chemical compound COC(=O)CC1CC(C=O)OC(C)(C)O1 HQSOLRBHGJZPST-UHFFFAOYSA-N 0.000 description 1
IOBOLJSHLCWRQV-UHFFFAOYSA-N methyl 2-[2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxan-4-yl]acetate Chemical compound O1C(C)(C)OC(CC(=O)OC)CC1C=CC1=CC=CC=C1 IOBOLJSHLCWRQV-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
210000001589 microsome Anatomy 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
150000004682 monohydrates Chemical class 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000002560 nitrile group Chemical group 0.000 description 1
239000002687 nonaqueous vehicle Substances 0.000 description 1
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
239000008188 pellet Substances 0.000 description 1
230000010412 perfusion Effects 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
239000012071 phase Substances 0.000 description 1
PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
235000011007 phosphoric acid Nutrition 0.000 description 1
230000004962 physiological condition Effects 0.000 description 1
YARAJYKHRCCDLG-UHFFFAOYSA-N phytuberin Chemical compound C1C(C(C)(C)OC(=O)C)CCC2(C)COC3(C)C21OC=C3 YARAJYKHRCCDLG-UHFFFAOYSA-N 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
229920002223 polystyrene Polymers 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
150000003217 pyrazoles Chemical class 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
206010037844 rash Diseases 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000011946 reduction process Methods 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
PRGXNXSWHFLCJT-UHFFFAOYSA-M sodium;8-(1-ethyltetrazol-5-yl)-9,9-bis(4-fluorophenyl)-3,5-dihydroxynona-6,8-dienoate Chemical compound [Na+].CCN1N=NN=C1C(C=CC(O)CC(O)CC([O-])=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 PRGXNXSWHFLCJT-UHFFFAOYSA-M 0.000 description 1
VGWABONFQSJGCE-UHFFFAOYSA-M sodium;9,9-bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound [Na+].CC1=CC(C)=CC=C1C(C=1C(=CC(C)=CC=1)C)=C(C=CC(O)CC(O)CC([O-])=O)C1=NN=NN1C VGWABONFQSJGCE-UHFFFAOYSA-M 0.000 description 1
238000000935 solvent evaporation Methods 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
BATOPAZDIZEVQF-UHFFFAOYSA-N sorbic aldehyde Natural products CC=CC=CC=O BATOPAZDIZEVQF-UHFFFAOYSA-N 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
239000000758 substrate Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000007910 systemic administration Methods 0.000 description 1
239000002278 tabletting lubricant Substances 0.000 description 1
RCWOYGUJLXGCOP-UHFFFAOYSA-N tert-butyl 9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound FC1=CC(C)=CC=C1C(C=1C(=CC(C)=CC=1)F)=C(C=CC(O)CC(O)CC(=O)OC(C)(C)C)C1=NN=NN1C RCWOYGUJLXGCOP-UHFFFAOYSA-N 0.000 description 1
LWGWDKMHPJJYAD-UHFFFAOYSA-N tert-butyl 9,9-bis(2-fluoro-4-methylphenyl)-5-hydroxy-8-(1-methyltetrazol-5-yl)-3-oxonona-6,8-dienoate Chemical compound FC1=CC(C)=CC=C1C(C=1C(=CC(C)=CC=1)F)=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)C1=NN=NN1C LWGWDKMHPJJYAD-UHFFFAOYSA-N 0.000 description 1
RGECIZXUZRECEC-UHFFFAOYSA-N tert-butyl 9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound CC1=CC(F)=CC=C1C(C=1C(=CC(F)=CC=1)C)=C(C=CC(O)CC(O)CC(=O)OC(C)(C)C)C1=NN=NN1C RGECIZXUZRECEC-UHFFFAOYSA-N 0.000 description 1
CEKTUAWFENQTEG-UHFFFAOYSA-N tert-butyl 9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxo-8-(2-trityltetrazol-5-yl)nona-6,8-dienoate Chemical compound N1=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)N=C1C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 CEKTUAWFENQTEG-UHFFFAOYSA-N 0.000 description 1
WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
238000010998 test method Methods 0.000 description 1
DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002627 tracheal intubation Methods 0.000 description 1
238000012546 transfer Methods 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
229910052722 tritium Inorganic materials 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
230000035899 viability Effects 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Obesity (AREA)
Diabetes (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Hematology (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Steroid Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

AT0046188A 1987-02-25 1988-02-24 Antihypercholesterinaemische tetrazol-verbindungen AT395589B (de)

Priority Applications (2)

Application Number	Priority Date	Filing Date	Title
AT0038292A AT401175B (de)	1987-02-25	1992-02-28	Neue tetrazol-verbindungen und verfahren zu ihrer herstellung
AT0037992A AT401518B (de)	1987-02-25	1992-02-28	Neue tetrazol-verbindungen und verfahren zu ihrer herstellung

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US1854287A	1987-02-25	1987-02-25
US07/151,513 US4897490A (en)	1987-02-25	1988-02-18	Antihypercholesterolemic tetrazole compounds

Publications (2)

Publication Number	Publication Date
ATA46188A ATA46188A (de)	1992-06-15
AT395589B true AT395589B (de)	1993-01-25

Family

ID=26691223

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
AT0046188A AT395589B (de)	1987-02-25	1988-02-24	Antihypercholesterinaemische tetrazol-verbindungen

Country Status (31)

Country	Link
US (1)	US4897490A (pt)
JP (1)	JP2603324B2 (pt)
KR (1)	KR960001203B1 (pt)
CN (1)	CN1026110C (pt)
AT (1)	AT395589B (pt)
AU (1)	AU1395088A (pt)
BE (1)	BE1002116A3 (pt)
CA (1)	CA1328268C (pt)
CH (1)	CH676848A5 (pt)
CS (1)	CS271481B2 (pt)
DE (1)	DE3805801C2 (pt)
DK (1)	DK174822B1 (pt)
EG (1)	EG18341A (pt)
ES (2)	ES2010246A6 (pt)
FI (1)	FI96601C (pt)
FR (1)	FR2612924B1 (pt)
GR (1)	GR1000472B (pt)
HU (3)	HU204038B (pt)
IE (1)	IE61619B1 (pt)
IL (1)	IL85529A (pt)
IT (1)	IT1216751B (pt)
LU (1)	LU87144A1 (pt)
MX (1)	MX9202847A (pt)
MY (1)	MY103214A (pt)
NL (1)	NL8800465A (pt)
NO (1)	NO169438C (pt)
NZ (1)	NZ223620A (pt)
PT (1)	PT86820B (pt)
SE (1)	SE503618C2 (pt)
WO (1)	WO1988006584A1 (pt)
YU (1)	YU36388A (pt)

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* Cited by examiner, † Cited by third party
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DE3741509A1 (de) *	1987-12-08	1989-06-22	Hoechst Ag	Verfahren zur herstellung optisch aktiver 3-desmethylmevalonsaeurederivate sowie zwischenprodukte
US4824959A (en) *	1988-02-18	1989-04-25	Bristol-Myers Company	Intermediates for antihypercholesterolemic tetrazole compounds
GB2244706B (en) *	1988-02-18	1992-07-15	Bristol Myers Co	Preparation of antihypercholesterolemic tetrazole intermediates
US4870187A (en) *	1988-08-23	1989-09-26	Bristol-Myers Company	Antihypercholesterolemic tetrazol-1-yl compounds
US5010205A (en) *	1988-08-23	1991-04-23	Bristol-Myers Company	Antihypercholesterolemic tetrazol-1-yl intermediates
US4927944A (en) *	1988-08-25	1990-05-22	Bristol-Myers Company	Antihypercholesterolemic nitrile compounds
FI94339C (fi)	1989-07-21	1995-08-25	Warner Lambert Co	Menetelmä farmaseuttisesti käyttökelpoisen /R-(R,R)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
US5413935A (en) *	1991-04-24	1995-05-09	E. R. Squibb & Sons, Inc.	Process for selecting an enantiomer of a hydroxy lactone using pseudomonas lipase
US5134155A (en) *	1991-08-08	1992-07-28	Ortho Pharmaceutical Corporation	Tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds and their use as HMG-coA reductase inhibitors
US5986095A (en) *	1992-01-06	1999-11-16	E.R. Squibb & Sons, Inc.	Enantioselective preparation of halophenyl alcohols and acylates
US5278313A (en) *	1992-03-27	1994-01-11	E. R. Squibb & Sons, Inc.	Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
US5324662A (en) *	1992-05-15	1994-06-28	E. R. Squibb & Sons, Inc.	Stereoselective microbial or enzymatic reduction of 3,5-dioxo esters to 3-hydroxy-5-oxo, 3-oxo-5-hydroxy, and 3,5-dihydroxy esters
US5284957A (en) *	1992-09-03	1994-02-08	Eli Lilly And Company	Excitatory amino acid receptor antagonists
JPH06329679A (ja) *	1993-01-20	1994-11-29	Nissan Chem Ind Ltd	光学活性β−アミノアルコキシボラン錯体
CA2137049A1 (en) *	1993-12-15	1995-06-16	John K. Thottathil	Amino acid salts of and methods for preparing antihypercholesterolemic tetrazole compounds
DE19714343A1 (de)	1997-04-08	1998-10-15	Bayer Ag	Chromatographische Enantiomerentrennung von Lactonen
ATE360608T1 (de) *	1997-12-19	2007-05-15	Pfizer Ireland Pharmaceuticals	Verfahren zur herstellung von 1,3-diolen
DE10216967A1 (de) *	2002-04-16	2003-11-13	Bayer Ag	Verfahren zur Herstellung spezieller aromatischer Aldehyde
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- 1988-02-24 FR FR888802211A patent/FR2612924B1/fr not_active Expired - Lifetime
- 1988-02-24 ES ES8800532A patent/ES2010246A6/es not_active Expired
- 1988-02-24 SE SE8800638A patent/SE503618C2/xx not_active IP Right Cessation
- 1988-02-24 NZ NZ223620A patent/NZ223620A/en unknown
- 1988-02-24 NO NO880809A patent/NO169438C/no not_active IP Right Cessation
- 1988-02-24 JP JP63502491A patent/JP2603324B2/ja not_active Expired - Lifetime
- 1988-02-24 KR KR1019880002010A patent/KR960001203B1/ko not_active IP Right Cessation
- 1988-02-24 DE DE3805801A patent/DE3805801C2/de not_active Expired - Lifetime
- 1988-02-24 CA CA000559667A patent/CA1328268C/en not_active Expired - Fee Related
- 1988-02-24 CS CS881180A patent/CS271481B2/cs not_active IP Right Cessation
- 1988-02-24 HU HU88886A patent/HU204038B/hu unknown
- 1988-02-24 MY MYPI88000178A patent/MY103214A/en unknown
- 1988-02-24 DK DK198800972A patent/DK174822B1/da not_active IP Right Cessation
- 1988-02-24 NL NL8800465A patent/NL8800465A/nl not_active Application Discontinuation
- 1988-02-24 AU AU13950/88A patent/AU1395088A/en not_active Abandoned
- 1988-02-24 HU HU90669A patent/HU203329B/hu unknown
- 1988-02-24 CH CH692/88A patent/CH676848A5/de not_active IP Right Cessation
- 1988-02-24 FI FI880869A patent/FI96601C/fi active IP Right Grant
- 1988-02-24 GR GR880100101A patent/GR1000472B/el not_active IP Right Cessation
- 1988-02-24 PT PT86820A patent/PT86820B/pt not_active IP Right Cessation
- 1988-02-24 IT IT8819525A patent/IT1216751B/it active
- 1988-02-24 IE IE50188A patent/IE61619B1/en not_active IP Right Cessation
- 1988-02-24 AT AT0046188A patent/AT395589B/de not_active IP Right Cessation
- 1988-02-24 WO PCT/US1988/000462 patent/WO1988006584A1/en unknown
- 1988-02-24 EG EG107/88A patent/EG18341A/xx active
- 1988-02-24 IL IL85529A patent/IL85529A/xx not_active IP Right Cessation
- 1988-02-24 HU HU896737A patent/HU204516B/hu unknown
- 1988-02-25 LU LU87144A patent/LU87144A1/fr unknown
- 1988-02-25 BE BE8800220A patent/BE1002116A3/fr not_active IP Right Cessation
- 1988-02-25 YU YU00363/88A patent/YU36388A/xx unknown
- 1988-02-25 CN CN88100911A patent/CN1026110C/zh not_active Expired - Lifetime
1989
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1992
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Also Published As

Publication number	Publication date
CN1026110C (zh)	1994-10-05
FI96601C (fi)	1996-07-25
DK174822B1 (da)	2003-12-08
SE8800638D0 (sv)	1988-02-24
WO1988006584A1 (en)	1988-09-07
LU87144A1 (fr)	1988-09-20
MX9202847A (es)	1992-06-30
CA1328268C (en)	1994-04-05
NL8800465A (nl)	1988-09-16
NO880809D0 (no)	1988-02-24
FR2612924A1 (fr)	1988-09-30
IT1216751B (it)	1990-03-08
IE880501L (en)	1988-08-25
MY103214A (en)	1993-05-29
HU900669D0 (en)	1990-06-28
ATA46188A (de)	1992-06-15
ES2010246A6 (es)	1989-11-01
HU896737D0 (en)	1990-02-28
HUT47259A (en)	1989-02-28
FI880869A0 (fi)	1988-02-24
IT8819525A0 (it)	1988-02-24
GR880100101A (en)	1988-12-16
YU36388A (en)	1989-10-31
KR960001203B1 (ko)	1996-01-24
FI880869A (fi)	1988-08-26
NO169438B (no)	1992-03-16
HU203329B (en)	1991-07-29
DE3805801C2 (de)	2001-03-01
DK97288A (da)	1988-08-26
NZ223620A (en)	1991-07-26
IL85529A (en)	1993-01-31
HU204516B (en)	1992-01-28
HU204038B (en)	1991-11-28
GR1000472B (el)	1992-07-30
JP2603324B2 (ja)	1997-04-23
FR2612924B1 (fr)	1991-01-11
CN88100911A (zh)	1988-09-28
JPH01502269A (ja)	1989-08-10
AU1395088A (en)	1988-09-26
KR880009947A (ko)	1988-10-06
EG18341A (en)	1993-08-30
PT86820B (pt)	1995-03-01
PT86820A (pt)	1989-02-28
IL85529A0 (en)	1988-08-31
BE1002116A3 (fr)	1990-07-10
CS118088A2 (en)	1989-08-14
SE8800638L (sv)	1988-09-21
CH676848A5 (pt)	1991-03-15
US4897490A (en)	1990-01-30
SE503618C2 (sv)	1996-07-15
DK97288D0 (da)	1988-02-24
NO169438C (no)	1992-06-24
NO880809L (no)	1988-08-26
CS271481B2 (en)	1990-10-12
DE3805801A1 (de)	1988-09-08
FI96601B (fi)	1996-04-15
IE61619B1 (en)	1994-11-16
ES2026746A6 (es)	1992-05-01

Publication	Publication Date	Title
AT395589B (de)	1993-01-25	Antihypercholesterinaemische tetrazol-verbindungen
US5447954A (en)	1995-09-05	Phenylderivate as inhibitors of ATP citrate lyase
AU628198B2 (en)	1992-09-10	(R-(RR))-2-(4-fluorohpenyl)-beta,delta-dihydroxy-5-(1- methylethyl-3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1- heptanoic acid, its lactone form and salts thereof
DE68904083T2 (de)	1993-06-03	Hmg-coa-reduktaseinhibitoren.
EP0491226B1 (de)	1996-08-14	Substituierte Pyridyl-dihydroxy-heptensäure und deren Salze
DE3904899A1 (de)	1989-08-31	Zwischenprodukte zur herstellung von antihypercholesterinaemischen tetrazol-verbindungen
US4870187A (en)	1989-09-26	Antihypercholesterolemic tetrazol-1-yl compounds
EP0300249B1 (de)	1993-02-03	7-[1H-Pyrrol-3-yl]-substituierte 3,5-Dihydroxy-heptansäuren, ihre entsprechenden delta-Lactone und Salze, Verfahren zu ihrer Herstellung, ihre Verwendung als Arzneimittel, pharmazeutische Präparate und Zwischenprodukte
DE3805789C2 (de)	2001-05-31	Zwischenprodukte und Verfahren zur Herstellung von antihypercholesterinämischen Tetrazolverbindungen
EP0468258A1 (de)	1992-01-29	Substituierte Pyrido-oxazine
US5028730A (en)	1991-07-02	Antihypercholesterolemic nitrile compounds
HUT52047A (en)	1990-06-28	Process for producing disubstituted pyrrol derivatives and pharmaceutical compositions containing them
AT401263B (de)	1996-07-25	Verfahren zur herstellung neuer tetrazolverbindungen
DD279880A5 (de)	1990-06-20	Verfahren zur herstellung neuer tetrazolverbindungen
US5010205A (en)	1991-04-23	Antihypercholesterolemic tetrazol-1-yl intermediates
US5070206A (en)	1991-12-03	Tetrazol-1-yl containing intermediates
US4981991A (en)	1991-01-01	Antihypercholesterolemic nitrile compounds
DD297818A5 (de)	1992-01-23	Neue tetrazol-zwischenprodukte, ihre herstellung und verwendung zur herstellug von antihypercholesterinaemischen mitteln
US5068346A (en)	1991-11-26	Tetrazole compounds
US4939265A (en)	1990-07-03	Intermediates and process for the preparation of antihypercholesterolemic tetrazole compounds
KR0149634B1 (ko)	1998-10-15	3,5-디하이드록시헵트-6-인산의 7-치환된 유도체로부터 제조된 락톤,이의 제조방법 및 이를 포함하는 약제학적 생성물

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Date	Code	Title
1990-02-15	UEP	Publication of translation of european patent specification
1994-02-15	REN	Ceased due to non-payment of the annual fee
2008-11-15	ELA	Expired due to lapse of time